(1) Field of the Invention
The present invention relates to a process for the preparation of 2-thiaquinolizidines which are selective α-glycosidase inhibitors having the formula:
where x is 0 to 3. In particular, the present invention relates to thiaquinolizidines which are derived from a mono-, or di-glycoside with protected hydroxyl groups, if present, by a synthetic route which reacts a 6-halo-5-ulosonic acid ester with a 2-aminoalkanethiol to form a 6-membered thiazine ring in which the nitrogen is in the form of a hemiaminal or imine and then reduction of the hemiaminal or imine to form an intermediate amino acid ester which cyclizes to form a lactam. Reduction of the lactam and deprotection of any protected hydroxyl groups forms the 2-thiaquinolizidine.
(2) Description of Related Art
Mono- and dihydroxy substituted 2-thiaquinolizidines are known. They are described in Winterfeld, K., et al., 1-(2-Chloroethyl)-2-chloromethylpiperidine. Chemische Berichte 92 1510-17 (1959); Rink, M., et al., Synthesis of 2-thiaquinolizidine and its S,S-dioxide. Arch. Pharm. 292 165-9 (1959); Gorlach, G. A., et al., New Synthesis of plezhicil. Meditsinskaya Promyshlennost SSSR 13 (No. 4), 35-40 (1959); Rink, Melanie, et al., Synthesis of 2-thiaquinolizidine. Naturwissenschaften 44 559 (1957); and Hadley, Michael Stewart, et al., Pharmaceutically active compounds. Eur. Pat. Appl. (1981), 71 pp. CODEN:EPXXDW EP 34015 A2 19810819 CAN 96:6743 AN 1982:6743 CAPLUS. They are used as intermediates to other compounds.
Compounds incorporating 5-aza-1-deoxyglycosides or a 1,5-imino-1,5-dideoxyalditol substructure are known in the art. They are generally aza-sugars or iminoalditols. Examples are castanospermine 1 and deoxynojirimycin 2. These compounds are often potent glycosidase or glycosyltransferase inhibitors.

Despite their promise, glycosidase inhibitors such as castanospermine 1, and deoxynojirimycin 2, have not realized their full clinical potential. This is largely because of a lack of commercially viable syntheses and difficulty in preparing a comprehensive palette of variant structures. In some cases such as deoxynojirimycin there is also the problem of too low specificity for a particular enzyme (Legler, G., Adv. Carbohydr. Chem. Biochem. 48 319-384 (1990); and Vandenbroek, L. A. G. M., et al., Rec. Trav. Chim. Pays Bas 112 82 (1993)). Iminoalditols are typically plant alkaloids and many of the possible drug candidates are available in only small exploratory amounts. The potential medical applications for these compounds and their derivatives are numerous and range from diabetes (Truscheit, E., et al., Angew. Chem. Int. Ed. Engl. 20 744 (1981); Anzeveno, P. B., et al., J. Org. Chem. 54 2539 (1989); Witczak, Z. J., Carbohydrates as New and Old Targets for Future Drug Design. In Carbohydrates in Drug Design; Witczak, Z. J., Ed.; Marcel Dekker Inc.; New York Page 1 (1997); and Platt, F. M., et al., Science 276 428 (1997)) and other metabolic disorders through antimicrobials (Karpas, A., et al., Proc. Natl. Acad. Sci. U.S.A. 85 9229 (1988); Fleet, G. W. J., et al., FEBS Lett. 237, 128 (1988); Taylor, D. L., et al., AIDS 5, 693 (1991); Hirsh, M. S., U.S. Pat. No. 5,011,826 (1991); and Rohrschneider, L. R., U.S. Pat. No. 5,643,888 (1997)), cancer (Gross, P. E., et al., Clin. Cancer Res. 1, 935 (1995)), autoimmune diseases (Kino, I., et al., J. Antibiot. 38, 936 (1985); Cenci di Bello, I., et al., Biochem. J. 259, 855 (1989); Elbein, A. D. FASEB J. 5, 3055 (1991); Goss, P. E., et al., Clin. Cancer Res. 1, 935 (1995); Das, P. C., et al., Oncol. Res. 7, 425 (1995); and Elbein, A. D., et al., In Iminosugars as Glycosidase Inhibitors; Stutz, A. E., Ed.; Wiley-VCH: Weinheim, pp 216-251 and references therein (1999)), neurological (Molyneux, R. J., et al., J. Nat. Prod. 58, 878 (1995)) and metabolic (Robinson, K. M., et al., Diabetes 40, 825 (1991); and Balfour, J. A., et al., Drugs 46 1025 (1993)) disorders. Because of their rigidity and the added interaction of the second ring, bicyclic systems such as in compound 1 are especially interesting.